Picotamide protects mice from death in a pulmonary embolism model by a mechanism independent from thromboxane suppression.
We have previously characterized the new antiplatelet agent picotamide as a dual thromboxane synthase inhibitor/thromboxane A2 receptor antagonist in human platelets. We have now studied the antithrombotic activity of this drug in a simple animal model of lung platelet thromboembolism in the mouse. Picotamide, given i.p. 1 hr before the thrombotic challenge, protected mice from death caused by the i.v. injection of collagen plus epinephrine in a dose-dependent way; the dose reducing mortality by 50% was 277 mg/kg while for aspirin it was 300 mg/kg. Picotamide was also able to reduce the mortality provoked by the i.v. injection of the stable TxA2 mimetic U46619; BM 13.505, a pure TxA2-receptor blocker, was also effective while aspirin was totally inactive. Picotamide, finally, reduced the lethal consequences of the i.v. injection of a 12.5% suspension of hardened rat red blood cells, a model in which platelets are not involved; aspirin was totally ineffective in this model while nicardipine, a calcium channel blocker, was active. Picotamide did not inhibit the formation of TxB2 in serum at any of the doses tested (100 to 750 mg/kg i.p.) while it did enhance significantly PGI2-synthesis from mice aortae and, even more, from mice lungs. The i.v. administration of picotamide (250 mg/kg 2 min before the thrombotic challenge) lead to a strong inhibition of serum TxB2 (-84.6%) and was associated with a higher antithrombotic effect.(ABSTRACT TRUNCATED AT 250 WORDS)
Gresele
P
P
Istituto di Semeiotica Medica, University of Perugia, Italy.
Corona
C
C
Alberti
P
P
Nenci
G G
GG
D000818:Animals; D001241:Aspirin / Q000627:therapeutic use; D004195:Disease Models, Animal; D011464:Epoprostenol / Q000097:blood; D008297:Male; D051379:Mice; D010795:Phthalic Acids / Q000627:therapeutic use*; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D010976:Platelet Count / Q000187:drug effects; D011655:Pulmonary Embolism / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D013929:Thromboxane B2 / Q000096:biosynthesis* / Q000097:blood
D010795:Phthalic Acids; D010975:Platelet Aggregation Inhibitors; D013929:Thromboxane B2; C011581:picotamide; D011464:Epoprostenol; D001241:Aspirin